Overview

The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [6-7]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [33] and the vanilloid TRPV1 ligand-gated nonselective cation channel [37]. The receptors for the cysteinyl-leukotrienes (i.e.LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [7]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [16,39,44], GPR17 [9] and GPR99 [29].

Comments

The FPR2/ALX receptor (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene and Lipoxin Receptors [7]) are activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A4 (LXA4) and 15-epi-LXA4 (aspirin triggered lipoxin A4, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [8] as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides [11,46]. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor [50]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [56,58]. The agonist activity of the lipid mediators described has been questioned [22,47], which may derive from batch-to-batch differences, partial agonism or biased agonism. A receptor selective for LXB4 has been suggested from functional studies [1,36,51]. Recent results from Cooray et al. (2013) [11] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages.

Oxoeicosanoid receptors (OXE, nomenclature agreed by the NC-IUPHAR subcommittee on Oxoeicosanoid Receptors [5]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as docosahexaenoic acid and EPA, acted as receptor antagonists [25].